Aryl hydrocarbon receptor ligands in cancer: friend and foe (original) (raw)
Bersten, D. C., Sullivan, A. E., Peet, D. J. & Whitelaw, M. L. bHLH-PAS proteins in cancer. Nature Rev. Cancer13, 827–841 (2013). CAS Google Scholar
Poland, A., Palen, D. & Glover, E. Tumour promotion by TCDD in skin of HRS/J hairless mice. Nature300, 271–273 (1982). CASPubMed Google Scholar
Sato, S. et al. Low-dose dioxins alter gene expression related to cholesterol biosynthesis, lipogenesis, and glucose metabolism through the aryl hydrocarbon receptor-mediated pathway in mouse liver. Toxicol. Appl. Pharmacol.229, 10–19 (2008). CASPubMed Google Scholar
Denison, M. S., Soshilov, A. A., He, G., DeGroot, D. E. & Zhao, B. Exactly the same but different: promiscuity and diversity in the molecular mechanisms of action of the aryl hydrocarbon (dioxin) receptor. Toxicol. Sci.124, 1–22 (2011). CASPubMedPubMed Central Google Scholar
Zhao, B. et al. Common commercial and consumer products contain activators of the aryl hydrocarbon (dioxin) receptor. PLoS ONE8, e56860 (2013). CASPubMedPubMed Central Google Scholar
Jeuken, A. et al. Activation of the Ah receptor by extracts of dietary herbal supplements, vegetables, and fruits. J. Agr. Food Chem.51, 5478–5487 (2003). CAS Google Scholar
Hu, W., Sorrentino, C., Denison, M. S., Kolaja, K. & Fielden, M. R. Induction of Cyp1a1 is a nonspecific biomarker of aryl hydrocarbon receptor activation: results of large scale screening of pharmaceuticals and toxicants in vivo and in vitro. Mol. Pharmacol.71, 1475–1486 (2007). CASPubMed Google Scholar
Van der Heiden, E. et al. Food flavonoid aryl hydrocarbon receptor-mediated agonistic/antagonistic/synergic activities in human and rat reporter gene assays. Anal. Chim. Acta637, 337–345 (2009). CASPubMed Google Scholar
Zhang, S., Qin, C. & Safe, S. H. Flavonoids as aryl hydrocarbon receptor agonists/antagonists: effects of structure and cell context. Environ. Health Perspect.111, 1877–1882 (2003). CASPubMedPubMed Central Google Scholar
Bjeldanes, L. F., Kim, J. Y., Grose, K. R., Bartholomew, J. C. & Bradfield, C. A. Aromatic hydrocarbon responsiveness-receptor agonists generated from indole-3-carbinol in vitro and in vivo: comparisons with 2,3,7,8-tetrachlorodibenzo-_p_-dioxin. Proc. Natl Acad. Sci. USA88, 9543–9547 (1991). This study shows that the high-affinity AHR ligand indolo[3,2b]carbazole is producedin vivofrom indole-3-carbinol. CASPubMedPubMed Central Google Scholar
Jin, U. H. et al. Microbiome-derived tryptophan metabolites and their aryl hydrocarbon receptor-dependent agonist and antagonist activities. Mol. Pharmacol.85, 777–788 (2014). PubMedPubMed Central Google Scholar
Zelante, T. et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity39, 372–385 (2013). CASPubMed Google Scholar
Fukumoto, S. et al. Identification of a probiotic bacteria-derived activator of the aryl hydrocarbon receptor that inhibits colitis. Immunol. Cell Biol.92, 460–465 (2014). CASPubMed Google Scholar
Magiatis, P. et al. Malassezia yeasts produce a collection of exceptionally potent activators of the Ah (dioxin) receptor detected in diseased human skin. J. Invest. Dermatol.133, 2023–2030 (2013). CASPubMedPubMed Central Google Scholar
van den Bogaard, E. H. et al. Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis. J. Clin. Invest.123, 917–927 (2013). CASPubMedPubMed Central Google Scholar
Oesch-Bartlomowicz, B. et al. Aryl hydrocarbon receptor activation by cAMP versus dioxin: divergent signaling pathways. Proc. Natl Acad. Sci. USA102, 9218–9223 (2005). CASPubMedPubMed Central Google Scholar
Ikuta, T. et al. Nucleocytoplasmic shuttling of the aryl hydrocarbon receptor. J. Biochem.127, 503–509 (2000). CASPubMed Google Scholar
DiNatale, B. C. et al. Ah receptor antagonism represses head and neck tumor cell aggressive phenotype. Mol. Cancer Res.10, 1369–1379 (2012). This study demonstrates that AHR antagonism inhibits constitutive AHR-mediated IL-6 production and migration, and the invasive phenotype in head and neck squamous cell carcinoma cells. CASPubMedPubMed Central Google Scholar
Han, Z. et al. Aryl hydrocarbon receptor mediates laminar fluid shear stress-induced CYP1A1 activation and cell cycle arrest in vascular endothelial cells. Cardiovasc. Res.77, 809–818 (2008). CASPubMed Google Scholar
Conway, D. E. et al. Expression of CYP1A1 and CYP1B1 in human endothelial cells: regulation by fluid shear stress. Cardiovasc. Res.81, 669–677 (2009). CASPubMedPubMed Central Google Scholar
Murray, I. A. et al. Evidence that ligand binding is a key determinant of Ah receptor-mediated transcriptional activity. Arch. Biochem. Biophys.442, 59–71 (2005). CASPubMed Google Scholar
Bock, K. W. & Kohle, C. Ah receptor- and TCDD-mediated liver tumor promotion: clonal selection and expansion of cells evading growth arrest and apoptosis. Biochem. Pharmacol.69, 1403–1408 (2005). CASPubMed Google Scholar
Knerr, S. & Schrenk, D. Carcinogenicity of 2,3,7,8-tetrachlorodibenzo-_p_-dioxin in experimental models. Mol. Nutr. Food Res.50, 897–907 (2006). CASPubMed Google Scholar
Naugler, W. E. et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science317, 121–124 (2007). CASPubMed Google Scholar
Kennedy, G. D. et al. Liver tumor promotion by 2,3,7,8-tetrachlorodibenzo-_p_-dioxin is dependent on the aryl hydrocarbon receptor and TNF/IL-1 receptors. Toxicol. Sci.140, 135–143 (2014). This study provides evidence that liver tumour promotion by activated AHR is dependent on inflammatory signalling. CASPubMedPubMed Central Google Scholar
He, G. et al. Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling. Cell155, 384–396 (2013). CASPubMedPubMed Central Google Scholar
DiNatale, B. C., Schroeder, J. C., Francey, L. J., Kusnadi, A. & Perdew, G. H. Mechanistic insights into the events that lead to synergistic induction of interleukin 6 transcription upon activation of the aryl hydrocarbon receptor and inflammatory signaling. J. Biol. Chem.285, 24388–24397 (2010). This study shows that AHR bound to DREs in the IL-6 promoter displaces HDAC1, leading to increased acetylation of RELA and synergistic induction of IL-6 transcription in the presence of an inflammatory signal. CASPubMedPubMed Central Google Scholar
Schlezinger, J. J. et al. Direct assessment of cumulative aryl hydrocarbon receptor agonist activity in sera from experimentally exposed mice and environmentally exposed humans. Environ. Health Perspect.118, 693–698 (2010). CASPubMed Google Scholar
Connor, K. T. et al. AH receptor agonist activity in human blood measured with a cell-based bioassay: evidence for naturally occurring AH receptor ligands in vivo. J. Expo. Sci. Environ. Epidemiol.18, 369–380 (2008). CASPubMed Google Scholar
Adachi, J. et al. Indirubin and indigo are potent aryl hydrocarbon receptor ligands present in human urine. J. Biol. Chem.276, 31475–31478 (2001). CASPubMed Google Scholar
Wincent, E. et al. The suggested physiologic aryl hydrocarbon receptor activator and cytochrome P4501 substrate 6-formylindolo[3,2-_b_]carbazole is present in humans. J. Biol. Chem.284, 2690–2696 (2009). CASPubMed Google Scholar
Mezrich, J. D. et al. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J. Immunol.185, 3190–3198 (2010). This is the first study to link the activation of AHR by kynurenine with the generation of TRegcells. CASPubMed Google Scholar
Pilotte, L. et al. Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase. Proc. Natl Acad. Sci. USA109, 2497–2502 (2012). CASPubMedPubMed Central Google Scholar
Stone, T. W., Stoy, N. & Darlington, L. G. An expanding range of targets for kynurenine metabolites of tryptophan. Trends Pharmacol. Sci.34, 136–143 (2013). CASPubMed Google Scholar
Opitz, C. A. et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature478, 197–203 (2011). This is a landmark study that correlates negative outcome in human brain cancer with levels of AHR and TDO2. CASPubMed Google Scholar
DiNatale, B. C. et al. Kynurenic acid is a potent endogenous aryl hydrocarbon receptor ligand that synergistically induces interleukin 6 in the presence of inflammatory signaling. Toxicol. Sci.115, 89–97 (2010). This is the first report of an IDO1 product as a potent endogenous human AHR ligand. CASPubMedPubMed Central Google Scholar
Schroeder, J. C. et al. The uremic toxin 3-indoxyl sulfate is a potent endogenous agonist for the human aryl hydrocarbon receptor. Biochemistry49, 393–400 (2010). CASPubMed Google Scholar
Niwa, T., Takeda, N., Tatematsu, A. & Maeda, K. Accumulation of indoxyl sulfate, an inhibitor of drug-binding, in uremic serum as demonstrated by internal-surface reversed-phase liquid chromatography. Clin. Chem.34, 2264–2267 (1988). CASPubMed Google Scholar
Meijers, B. K. et al. _p_-Cresyl sulfate and indoxyl sulfate in hemodialysis patients. Clin. J. Am. Soc. Nephrol.4, 1932–1938 (2009). CASPubMedPubMed Central Google Scholar
Sindhu, R. K. & Vaziri, N. D. Upregulation of cytochrome P450 1A2 in chronic renal failure: does oxidized tryptophan play a role? Adv. Exp. Med. Biol.527, 401–407 (2003). CASPubMed Google Scholar
Wong, G. et al. Time on dialysis and cancer risk after kidney transplantation. Transplantation95, 114–121 (2013). CASPubMed Google Scholar
Fan, Y. et al. The aryl hydrocarbon receptor functions as a tumor suppressor of liver carcinogenesis. Cancer Res.70, 212–220 (2010). CASPubMed Google Scholar
Ikuta, T. et al. ASC-associated inflammation promotes cecal tumorigenesis in aryl hydrocarbon receptor-deficient mice. Carcinogenesis34, 1620–1627 (2013). CASPubMed Google Scholar
Fritz, W. A., Lin, T. M., Cardiff, R. D. & Peterson, R. E. The aryl hydrocarbon receptor inhibits prostate carcinogenesis in TRAMP mice. Carcinogenesis28, 497–505 (2007). This study establishes that expression of AHR represses prostate carcinogenesis in TRAMP mice. CASPubMed Google Scholar
Moennikes, O. et al. A constitutively active dioxin/aryl hydrocarbon receptor promotes hepatocarcinogenesis in mice. Cancer Res.64, 4707–4710 (2004). CASPubMed Google Scholar
Andersson, P. et al. A constitutively active dioxin/aryl hydrocarbon receptor induces stomach tumors. Proc. Natl Acad. Sci. USA99, 9990–9995 (2002). This report shows that the expression of a constitutively active mutant AHR in transgenic mice induces the formation of stomach tumours. CASPubMedPubMed Central Google Scholar
Puga, A., Xia, Y. & Elferink, C. Role of the aryl hydrocarbon receptor in cell cycle regulation. Chem. Biol. Interact.141, 117–130 (2002). CASPubMed Google Scholar
John, K., Lahoti, T. S., Wagner, K., Hughes, J. M. & Perdew, G. H. The Ah receptor regulates growth factor expression in head and neck squamous cell carcinoma cell lines. Mol. Carcinog.53, 765–776 (2013). PubMedPubMed Central Google Scholar
Chuang, C. Y. et al. Up-regulation of osteopontin expression by aryl hydrocarbon receptor via both ligand-dependent and ligand-independent pathways in lung cancer. Gene492, 262–269 (2012). CASPubMed Google Scholar
Patel, R. D., Kim, D. J., Peters, J. M. & Perdew, G. H. The aryl hydrocarbon receptor directly regulates expression of the potent mitogen epiregulin. Toxicol. Sci.89, 75–82 (2006). CASPubMed Google Scholar
Roman, A. C., Carvajal-Gonzalez, J. M., Rico-Leo, E. M. & Fernandez-Salguero, P. M. Dioxin receptor deficiency impairs angiogenesis by a mechanism involving VEGF-A depletion in the endothelium and transforming growth factor-β overexpression in the stroma. J. Biol. Chem.284, 25135–25148 (2009). CASPubMedPubMed Central Google Scholar
Shigeishi, H. et al. Expression of epiregulin, a novel epidermal growth factor ligand associated with prognosis in human oral squamous cell carcinomas. Oncol. Rep.19, 1557–1564 (2008). CASPubMed Google Scholar
Wang, C. K. et al. Aryl hydrocarbon receptor activation and overexpression upregulated fibroblast growth factor-9 in human lung adenocarcinomas. Int. J. Cancer125, 807–815 (2009). CASPubMed Google Scholar
Nishimura, T. et al. Amphiregulin and epiregulin expression in neoplastic and inflammatory lesions in the colon. Oncol. Rep.19, 105–110 (2008). PubMed Google Scholar
Riese, D. J., 2nd & Cullum, R. L. Epiregulin: roles in normal physiology and cancer. Semin. Cell Dev. Biol.28, 49–56 (2014). CASPubMed Google Scholar
Zhu, Z. et al. Epiregulin is up-regulated in pancreatic cancer and stimulates pancreatic cancer cell growth. Biochem. Biophys. Res. Commun.273, 1019–1024 (2000). CASPubMed Google Scholar
Marlowe, J. L. & Puga, A. Aryl hydrocarbon receptor, cell cycle regulation, toxicity, and tumorigenesis. J. Cell Biochem.96, 1174–1184 (2005). CASPubMed Google Scholar
Elferink, C. J. Aryl hydrocarbon receptor-mediated cell cycle control. Prog. Cell Cycle Res.5, 261–267 (2003). PubMed Google Scholar
Vezina, C. M., Lin, T. M. & Peterson, R. E. AHR signaling in prostate growth, morphogenesis, and disease. Biochem. Pharmacol.77, 566–576 (2009). This study shows that human prostrate tumours with an aggressive phenotype exhibit enhanced nuclear localization of AHR. CASPubMed Google Scholar
Schlezinger, J. J. et al. A role for the aryl hydrocarbon receptor in mammary gland tumorigenesis. Biol. Chem.387, 1175–1187 (2006). CASPubMed Google Scholar
Feng, S., Cao, Z. & Wang, X. Role of aryl hydrocarbon receptor in cancer. Biochim. Biophys. Acta1836, 197–210 (2013). CASPubMed Google Scholar
Safe, S., Lee, S. O. & Jin, U. H. Role of the aryl hydrocarbon receptor in carcinogenesis and potential as a drug target. Toxicol. Sci.135, 1–16 (2013). CASPubMedPubMed Central Google Scholar
Spink, D. C., Johnson, J. A., Connor, S. P., Aldous, K. M. & Gierthy, J. F. Stimulation of 17 β-estradiol metabolism in MCF-7 cells by bromochloro- and chloromethyl-substituted dibenzo-_p_-dioxins and dibenzofurans: correlations with antiestrogenic activity. J. Toxicol. Environ. Health41, 451–466 (1994). CASPubMed Google Scholar
Wormke, M. et al. The aryl hydrocarbon receptor mediates degradation of estrogen receptor α through activation of proteasomes. Mol. Cell. Biol.23, 1843–1855 (2003). CASPubMedPubMed Central Google Scholar
Ohtake, F., Fujii-Kuriyama, Y. & Kato, S. AhR acts as an E3 ubiquitin ligase to modulate steroid receptor functions. Biochem. Pharmacol.77, 474–484 (2009). CASPubMed Google Scholar
Safe, S. & Wormke, M. Inhibitory aryl hydrocarbon receptor–estrogen receptor α cross-talk and mechanisms of action. Chem. Res. Toxicol.16, 807–816 (2003). CASPubMed Google Scholar
Madak-Erdogan, Z. & Katzenellenbogen, B. S. Aryl hydrocarbon receptor modulation of estrogen receptor α-mediated gene regulation by a multimeric chromatin complex involving the two receptors and the coregulator RIP140. Toxicol. Sci.125, 401–411 (2012). CASPubMed Google Scholar
Beischlag, T. V. & Perdew, G. H. ERα-AHR-ARNT protein-protein interactions mediate estradiol-dependent transrepression of dioxin-inducible gene transcription. J. Biol. Chem.280, 21607–21611 (2005). CASPubMed Google Scholar
Dohr, O., Vogel, C. & Abel, J. Different response of 2,3,7,8-tetrachlorodibenzo-_p_-dioxin (TCDD)-sensitive genes in human breast cancer MCF-7 and MDA-MB 231 cells. Arch. Biochem. Biophys.321, 405–412 (1995). CASPubMed Google Scholar
Stark, K. et al. Reactivation of estrogen receptor α by vorinostat sensitizes mesenchymal-like triple-negative breast cancer to aminoflavone, a ligand of the aryl hydrocarbon receptor. PLoS ONE8, e74525 (2013). CASPubMedPubMed Central Google Scholar
Wihlen, B., Ahmed, S., Inzunza, J. & Matthews, J. Estrogen receptor subtype- and promoter-specific modulation of aryl hydrocarbon receptor-dependent transcription. Mol. Cancer Res.7, 977–986 (2009). CASPubMed Google Scholar
Terashima, J., Habano, W., Gamou, T. & Ozawa, S. Induction of CYP1 family members under low-glucose conditions requires AhR expression and occurs through the nuclear translocation of AhR. Drug Metab. Pharmacokinet.26, 577–583 (2011). CASPubMed Google Scholar
Vorrink, S. U. & Domann, F. E. Regulatory crosstalk and interference between the xenobiotic and hypoxia sensing pathways at the AhR-ARNT-HIF1α signaling node. Chem. Biol. Interact.218, 82–88 (2014). CASPubMed Google Scholar
Hamouchene, H., Arlt, V. M., Giddings, I. & Phillips, D. H. Influence of cell cycle on responses of MCF-7 cells to benzo[_a_]pyrene. BMC Genomics12, 333 (2011). CASPubMedPubMed Central Google Scholar
Shin, S. et al. NRF2 modulates aryl hydrocarbon receptor signaling: influence on adipogenesis. Mol. Cell. Biol.27, 7188–7197 (2007). CASPubMedPubMed Central Google Scholar
Cho, Y. C., Zheng, W. & Jefcoate, C. R. Disruption of cell-cell contact maximally but transiently activates AhR-mediated transcription in 10T1/2 fibroblasts. Toxicol. Appl. Pharmacol.199, 220–238 (2004). CASPubMed Google Scholar
Ikuta, T., Kobayashi, Y. & Kawajiri, K. Cell density regulates intracellular localization of aryl hydrocarbon receptor. J. Biol. Chem.279, 19209–19216 (2004). CASPubMed Google Scholar
Diry, M. et al. Activation of the dioxin/aryl hydrocarbon receptor (AhR) modulates cell plasticity through a JNK-dependent mechanism. Oncogene25, 5570–5574 (2006). CASPubMed Google Scholar
Peng, T. L., Chen, J., Mao, W., Song, X. & Chen, M. H. Aryl hydrocarbon receptor pathway activation enhances gastric cancer cell invasiveness likely through a c-Jun-dependent induction of matrix metalloproteinase-9. BMC Cell Biol.10, 27 (2009). PubMedPubMed Central Google Scholar
Niermann, T., Schmutz, S., Erne, P. & Resink, T. Aryl hydrocarbon receptor ligands repress T-cadherin expression in vascular smooth muscle cells. Biochem. Biophys. Res. Commun.300, 943–949 (2003). CASPubMed Google Scholar
Dinatale, B. C. & Perdew, G. H. Ah receptor antagonism inhibits constitutive and cytokine inducible IL6 production in head and neck tumor cell lines. Mol. Carcinog.50, 173–183 (2011). CASPubMed Google Scholar
Bui, L. C. et al. Nedd9/Hef1/Cas-L mediates the effects of environmental pollutants on cell migration and plasticity. Oncogene28, 3642–3651 (2009). CASPubMed Google Scholar
Fernandez-Salguero, P. M. A remarkable new target gene for the dioxin receptor: The Vav3 proto-oncogene links AhR to adhesion and migration. Cell Adh Migr4, 172–175 (2010). PubMedPubMed Central Google Scholar
Ikuta, T. & Kawajiri, K. Zinc finger transcription factor Slug is a novel target gene of aryl hydrocarbon receptor. Exp. Cell Res.312, 3585–3594 (2006). This study shows that AHR exhibits increased nuclear localization at low cellular densities and participates in the induction and regulation of tumour cell invasion. CASPubMed Google Scholar
Belguise, K. et al. Green tea polyphenols reverse cooperation between c-Rel and CK2 that induces the aryl hydrocarbon receptor, slug, and an invasive phenotype. Cancer Res.67, 11742–11750 (2007). CASPubMed Google Scholar
Hsu, E. L. et al. A proposed mechanism for the protective effect of dioxin against breast cancer. Toxicol. Sci.98, 436–444 (2007). CASPubMed Google Scholar
Jin, U. H., Lee, S. O., Pfent, C. & Safe, S. The aryl hydrocarbon receptor ligand omeprazole inhibits breast cancer cell invasion and metastasis. BMC Cancer14, 498 (2014). PubMedPubMed Central Google Scholar
Hanahan, D. & Coussens, L. M. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell21, 309–322 (2012). CASPubMed Google Scholar
Fardel, O. Cytokines as molecular targets for aryl hydrocarbon receptor ligands: implications for toxicity and xenobiotic detoxification. Expert Opin. Drug Metab. Toxicol.9, 141–152 (2013). CASPubMed Google Scholar
Haarmann-Stemmann, T., Bothe, H. & Abel, J. Growth factors, cytokines and their receptors as downstream targets of arylhydrocarbon receptor (AhR) signaling pathways. Biochem. Pharmacol.77, 508–520 (2009). CASPubMed Google Scholar
Sekine, H. et al. Hypersensitivity of aryl hydrocarbon receptor-deficient mice to lipopolysaccharide-induced septic shock. Mol. Cell. Biol.29, 6391–6400 (2009). CASPubMedPubMed Central Google Scholar
Lahoti, T. S. et al. Aryl hydrocarbon receptor antagonism attenuates growth factor expression, proliferation, and migration in fibroblast-like synoviocytes from patients with rheumatoid arthritis. J. Pharmacol. Exp. Ther.348, 236–245 (2014). PubMedPubMed Central Google Scholar
Apetoh, L. et al. The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27. Nature Immunol.11, 854–861 (2010). This study shows that AHR promotes TRegcell production through binding to MAF and inducing the expression of IL-10 and IL-21. CAS Google Scholar
Hollingshead, B. D., Beischlag, T. V., Dinatale, B. C., Ramadoss, P. & Perdew, G. H. Inflammatory signaling and aryl hydrocarbon receptor mediate synergistic induction of interleukin 6 in MCF-7 cells. Cancer Res.68, 3609–3617 (2008). CASPubMedPubMed Central Google Scholar
Furman, D. P., Oshchepkova, E. A., Oshchepkov, D. Y., Shamanina, M. Y. & Mordvinov, V. A. Promoters of the genes encoding the transcription factors regulating the cytokine gene expression in macrophages contain putative binding sites for aryl hydrocarbon receptor. Comput. Biol. Chem.33, 465–468 (2009). CASPubMed Google Scholar
Vogel, C. F. et al. Aryl hydrocarbon receptor signaling regulates NF-κB RelB activation during dendritic-cell differentiation. Immunol. Cell Biol.91, 568–575 (2013). CASPubMedPubMed Central Google Scholar
Vogel, C. F. et al. Pathogenesis of aryl hydrocarbon receptor-mediated development of lymphoma is associated with increased cyclooxygenase-2 expression. Am. J. Pathol.171, 1538–1548 (2007). CASPubMedPubMed Central Google Scholar
Degner, S. C., Papoutsis, A. J., Selmin, O. & Romagnolo, D. F. Targeting of aryl hydrocarbon receptor-mediated activation of cyclooxygenase-2 expression by the indole-3-carbinol metabolite 3,3′-diindolylmethane in breast cancer cells. J. Nutr.139, 26–32 (2009). CASPubMedPubMed Central Google Scholar
Tian, Y., Ke, S., Denison, M. S., Rabson, A. B. & Gallo, M. A. Ah receptor and NF-κB interactions, a potential mechanism for dioxin toxicity. J. Biol. Chem.274, 510–515 (1999). This is the first report demonstrating that AHR can interact with NF-κB. CASPubMed Google Scholar
Vogel, C. F. et al. RelB, a new partner of aryl hydrocarbon receptor-mediated transcription. Mol. Endocrinol.21, 2941–2955 (2007). CASPubMed Google Scholar
Kim, D. W. et al. The RelA NF-κB subunit and the aryl hydrocarbon receptor (AhR) cooperate to transactivate the c-myc promoter in mammary cells. Oncogene19, 5498–5506 (2000). CASPubMed Google Scholar
Vogel, C. F., Sciullo, E. & Matsumura, F. Involvement of RelB in aryl hydrocarbon receptor-mediated induction of chemokines. Biochem. Biophys. Res. Commun.363, 722–726 (2007). CASPubMedPubMed Central Google Scholar
Vogel, C. F. et al. Interaction of aryl hydrocarbon receptor and NF-κB subunit RelB in breast cancer is associated with interleukin-8 overexpression. Arch. Biochem. Biophys.512, 78–86 (2011). CASPubMedPubMed Central Google Scholar
Zou, W. Regulatory T cells, tumour immunity and immunotherapy. Nature Rev. Immunol.6, 295–307 (2006). CAS Google Scholar
Darrasse-Jeze, G. & Podsypanina, K. How numbers, nature, and immune status of Foxp3 regulatory T-cells shape the early immunological events in tumor development. Front. Immunol.4, 292 (2013). CASPubMedPubMed Central Google Scholar
Marshall, N. B., Vorachek, W. R., Steppan, L. B., Mourich, D. V. & Kerkvliet, N. I. Functional characterization and gene expression analysis of CD4+ CD25+ regulatory T cells generated in mice treated with 2,3,7,8-tetrachlorodibenzo-_p_-dioxin. J. Immunol.181, 2382–2391 (2008). CASPubMed Google Scholar
Gandhi, R. et al. Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like and Foxp3+ regulatory T cells. Nature Immunol.11, 846–853 (2010). CAS Google Scholar
Funatake, C. J., Marshall, N. B. & Kerkvliet, N. I. 2,3,7,8-Tetrachlorodibenzo-_p_-dioxin alters the differentiation of alloreactive CD8+ T cells toward a regulatory T cell phenotype by a mechanism that is dependent on aryl hydrocarbon receptor in CD4+ T cells. J. Immunotoxicol5, 81–91 (2008). CASPubMed Google Scholar
Kerkvliet, N. I., Shepherd, D. M. & Baecher-Steppan, L. T lymphocytes are direct, aryl hydrocarbon receptor (AhR)-dependent targets of 2,3,7,8-tetrachlorodibenzo- _p_-dioxin (TCDD): AhR expression in both CD4+ and CD8+ T cells is necessary for full suppression of a cytotoxic T lymphocyte response by TCDD. Toxicol. Appl. Pharmacol.185, 146–152 (2002). This study provides the firstin vivoevidence that TCDD can directly suppress a cytotoxic T lymphocyte response. CASPubMed Google Scholar
Kerkvliet, N. I. et al. Activation of aryl hydrocarbon receptor by TCDD prevents diabetes in NOD mice and increases Foxp3+ T cells in pancreatic lymph nodes. Immunotherapy1, 539–547 (2009). CASPubMed Google Scholar
Benson, J. M. & Shepherd, D. M. Aryl hydrocarbon receptor activation by TCDD reduces inflammation associated with Crohn's disease. Toxicol. Sci.120, 68–78 (2011). CASPubMed Google Scholar
Singh, N. P. et al. Activation of aryl hydrocarbon receptor (AhR) leads to reciprocal epigenetic regulation of FoxP3 and IL-17 expression and amelioration of experimental colitis. PLoS ONE6, e23522 (2011). CASPubMedPubMed Central Google Scholar
Quintana, F. J. et al. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature453, 65–71 (2008). CASPubMed Google Scholar
Punj, S. et al. Benzimidazoisoquinolines: a new class of rapidly metabolized aryl hydrocarbon receptor (AhR) ligands that induce AhR-dependent Tregs and prevent murine graft-versus-host disease. PLoS ONE9, e88726 (2014). PubMedPubMed Central Google Scholar
Wang, H. K. et al. Dietary flavonoid naringenin induces regulatory T cells via an aryl hydrocarbon receptor mediated pathway. J. Agr. Food Chem.60, 2171–2178 (2012). CAS Google Scholar
Luster, M. I. et al. 1-amino-3,7,8-trichlorodibenzo-_p_-dioxin: a specific antagonist for TCDD-induced myelotoxicity. Biochem. Biophys. Res. Commun.139, 747–756 (1986). CASPubMed Google Scholar
Merchant, M., Arellano, L. & Safe, S. The mechanism of action of α-naphthoflavone as an inhibitor of 2,3,7,8-tetrachlorodibenzo-_p_-dioxin-induced CYP1A1 gene expression. Arch. Biochem. Biophys.281, 84–89 (1990). CASPubMed Google Scholar
Gasiewicz, T. A. & Rucci, G. α-naphthoflavone acts as an antagonist of 2,3,7,8-tetrachlorodibenzo-_p_-dioxin by forming an inactive complex with the Ah receptor. Mol. Pharmacol.40, 607–612 (1991). CASPubMed Google Scholar
Henry, E. C. et al. Flavone antagonists bind competitively with 2,3,7,8-tetrachlorodibenzo-_p_-dioxin (TCDD) to the aryl hydrocarbon receptor but inhibit nuclear uptake and transformation. Mol. Pharmacol.55, 716–725 (1999). CASPubMed Google Scholar
Murray, I. A. et al. Antagonism of aryl hydrocarbon receptor signaling by 6,2′,4′-trimethoxyflavone. J. Pharmacol. Exp. Ther.332, 135–144 (2010). CASPubMedPubMed Central Google Scholar
Ciolino, H. P., Daschner, P. J. & Yeh, G. C. Resveratrol inhibits transcription of CYP1A1 in vitro by preventing activation of the aryl hydrocarbon receptor. Cancer Res.58, 5707–5712 (1998). CASPubMed Google Scholar
Kim, S. H. et al. Novel compound 2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazo-phenyl)-amide (CH-223191) prevents 2,3,7,8-TCDD-induced toxicity by antagonizing the aryl hydrocarbon receptor. Mol. Pharmacol.69, 1871–1878 (2006). CASPubMed Google Scholar
Boitano, A. E. et al. Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science329, 1345–1348 (2010). This study reports the development of a high-affinity AHR antagonist that promotes the proliferation of human haematopoietic stem cellsin vitroand that demonstrates therapeutic potential. CASPubMedPubMed Central Google Scholar
Smith, K. J. et al. Identification of a high affinity ligand that exhibits complete Ah receptor antagonism. J. Pharmacol. Exp. Ther.338, 318–327 (2011). CASPubMedPubMed Central Google Scholar
Brembilla, N. C. et al. In vivo dioxin favors interleukin-22 production by human CD4+ T cells in an aryl hydrocarbon receptor (AhR)-dependent manner. PLoS ONE6, e18741 (2011). CASPubMedPubMed Central Google Scholar
Zhao, B., Degroot, D. E., Hayashi, A., He, G. & Denison, M. S. CH223191 is a ligand-selective antagonist of the Ah (Dioxin) receptor. Toxicol. Sci.117, 393–403 (2010). CASPubMedPubMed Central Google Scholar
Lewis, J. S. & Jordan, V. C. Selective estrogen receptor modulators (SERMs): mechanisms of anticarcinogenesis and drug resistance. Mutat. Res.591, 247–263 (2005). CASPubMed Google Scholar
Safe, S. & McDougal, A. Mechanism of action and development of selective aryl hydrocarbon receptor modulators for treatment of hormone-dependent cancers (Review). Int. J. Oncol.20, 1123–1128 (2002). CASPubMed Google Scholar
Steffan, R. J. et al. Synthesis and activity of substituted 4-(indazol-3-yl)phenols as pathway-selective estrogen receptor ligands useful in the treatment of rheumatoid arthritis. J. Med. Chem.47, 6435–6438 (2004). CASPubMed Google Scholar
Chadwick, C. C. et al. Identification of pathway-selective estrogen receptor ligands that inhibit NF-κB transcriptional activity. Proc. Natl Acad. Sci. USA102, 2543–2548 (2005). CASPubMedPubMed Central Google Scholar
Murray, I. A. et al. Evidence for ligand-mediated selective modulation of aryl hydrocarbon receptor activity. Mol. Pharmacol.77, 247–254 (2010). CASPubMedPubMed Central Google Scholar
Murray, I. A. et al. Development of a selective modulator of aryl hydrocarbon (Ah) receptor activity that exhibits anti-inflammatory properties. Chem. Res. Toxicol.23, 955–966 (2010). CASPubMedPubMed Central Google Scholar
Murray, I. A. et al. Suppression of cytokine-mediated complement factor gene expression through selective activation of the Ah receptor with 3′,4′-dimethoxy-α-naphthoflavone. Mol. Pharmacol.79, 508–519 (2011). CASPubMedPubMed Central Google Scholar
Astroff, B. et al. 6-Methyl-1,3,8-trichlorodibenzofuran as a 2,3,7,8-tetrachlorodibenzo-_p_-dioxin antagonist: inhibition of the induction of rat cytochrome P-450 isozymes and related monooxygenase activities. Mol. Pharmacol.33, 231–236 (1988). CASPubMed Google Scholar
Zacharewski, T. et al. 6-Methyl-1,3,8-trichlorodibenzofuran (MCDF) as an antiestrogen in human and rodent cancer cell lines: evidence for the role of the Ah receptor. Toxicol. Appl. Pharmacol.113, 311–318 (1992). CASPubMed Google Scholar
McDougal, A., Wilson, C. & Safe, S. Inhibition of 7,12-dimethylbenz[_a_]anthracene-induced rat mammary tumor growth by aryl hydrocarbon receptor agonists. Cancer Lett.120, 53–63 (1997). CASPubMed Google Scholar
Zhang, S. et al. The aryl hydrocarbon receptor as a target for estrogen receptor-negative breast cancer chemotherapy. Endocr. Relat. Cancer16, 835–844 (2009). CASPubMedPubMed Central Google Scholar
Zhang, S. et al. Aryl hydrocarbon receptor agonists induce microRNA-335 expression and inhibit lung metastasis of estrogen receptor negative breast cancer cells. Mol. Cancer Ther.11, 108–118 (2012). PubMed Google Scholar
Manchester, D. K., Gordon, S. K., Golas, C. L., Roberts, E. A. & Okey, A. B. Ah receptor in human placenta: stabilization by molybdate and characterization of binding of 2,3,7,8-tetrachlorodibenzo-_p_-dioxin, 3-methylcholanthrene, and benzo(a)pyrene. Cancer Res.47, 4861–4868 (1987). CASPubMed Google Scholar
Flaveny, C. A., Murray, I. A. & Perdew, G. H. Differential gene regulation by the human and mouse aryl hydrocarbon receptor. Toxicol. Sci.114, 217–225 (2010). CASPubMed Google Scholar
Forgacs, A. L., Dere, E., Angrish, M. M. & Zacharewski, T. R. Comparative analysis of temporal and dose-dependent TCDD-elicited gene expression in human, mouse, and rat primary hepatocytes. Toxicol. Sci.133, 54–66 (2013). CASPubMedPubMed Central Google Scholar
Black, M. B. et al. Cross-species comparisons of transcriptomic alterations in human and rat primary hepatocytes exposed to 2,3,7,8-tetrachlorodibenzo-_p_-dioxin. Toxicol. Sci.127, 199–215 (2012). CASPubMed Google Scholar
Flaveny, C., Reen, R. K., Kusnadi, A. & Perdew, G. H. The mouse and human Ah receptor differ in recognition of LXXLL motifs. Arch. Biochem. Biophys.471, 215–223 (2008). CASPubMedPubMed Central Google Scholar
Ramadoss, P. & Perdew, G. H. Use of 2-azido-3-[125I]iodo-7,8-dibromodibenzo-_p_-dioxin as a probe to determine the relative ligand affinity of human versus mouse aryl hydrocarbon receptor in cultured cells. Mol. Pharmacol.66, 129–136 (2004). CASPubMed Google Scholar
Flaveny, C. A., Murray, I. A., Chiaro, C. R. & Perdew, G. H. Ligand selectivity and gene regulation by the human aryl hydrocarbon receptor in transgenic mice. Mol. Pharmacol.75, 1412–1420 (2009). CASPubMedPubMed Central Google Scholar
Saito, R. et al. Aryl hydrocarbon receptor in breast cancer — a newly defined prognostic marker. Horm. Cancer5, 11–21 (2014). CASPubMed Google Scholar
Richmond, O. et al. The aryl hydrocarbon receptor is constitutively active in advanced prostate cancer cells. PLoS ONE9, e95058 (2014). PubMedPubMed Central Google Scholar
Yin, X. F., Chen, J., Mao, W., Wang, Y. H. & Chen, M. H. Downregulation of aryl hydrocarbon receptor expression decreases gastric cancer cell growth and invasion. Oncol. Rep.30, 364–370 (2013). CASPubMed Google Scholar
Su, J. M., Lin, P. & Chang, H. Prognostic value of nuclear translocation of aryl hydrocarbon receptor for non-small cell lung cancer. Anticancer Res.33, 3953–3961 (2013). PubMed Google Scholar
Liu, Z. et al. AhR expression is increased in hepatocellular carcinoma. J. Mol. Histol.44, 455–461 (2013). CASPubMed Google Scholar
Tanaka, G. et al. Induction and activation of the aryl hydrocarbon receptor by IL-4 in B cells. Int. Immunol.17, 797–805 (2005). CASPubMed Google Scholar
Vogel, C. F. et al. Cross-talk between aryl hydrocarbon receptor and the inflammatory response: a role for nuclear factor-κB. J. Biol. Chem.289, 1866–1875 (2014). CASPubMed Google Scholar
Beischlag, T. V., Luis Morales, J., Hollingshead, B. D. & Perdew, G. H. The aryl hydrocarbon receptor complex and the control of gene expression. Crit. Rev. Eukaryot. Gene Expr.18, 207–250 (2008). CASPubMedPubMed Central Google Scholar
Mellor, A. L. et al. Cutting edge: induced indoleamine 2,3 dioxygenase expression in dendritic cell subsets suppresses T cell clonal expansion. J. Immunol.171, 1652–1655 (2003). CASPubMed Google Scholar
Litzenburger, U. M. et al. Constitutive IDO expression in human cancer is sustained by an autocrine signaling loop involving IL-6, STAT3 and the AHR. Oncotarget5, 1038–1051 (2014). PubMedPubMed Central Google Scholar
Kolluri, S. K., Weiss, C., Koff, A. & Gottlicher, M. p27Kip1 induction and inhibition of proliferation by the intracellular Ah receptor in developing thymus and hepatoma cells. Genes Dev.13, 1742–1753 (1999). CASPubMedPubMed Central Google Scholar
Pang, P. H. et al. Molecular mechanisms of p21 and p27 induction by 3-methylcholanthrene, an aryl-hydrocarbon receptor agonist, involved in antiproliferation of human umbilical vascular endothelial cells. J. Cell. Physiol.215, 161–171 (2008). CASPubMed Google Scholar
Puga, A. et al. Aromatic hydrocarbon receptor interaction with the retinoblastoma protein potentiates repression of E2F-dependent transcription and cell cycle arrest. J. Biol. Chem.275, 2943–2950 (2000). CASPubMed Google Scholar
Barhoover, M. A., Hall, J. M., Greenlee, W. F. & Thomas, R. S. Aryl hydrocarbon receptor regulates cell cycle progression in human breast cancer cells via a functional interaction with cyclin-dependent kinase 4. Mol. Pharmacol.77, 195–201 (2010). CASPubMed Google Scholar
Denison, M. S. & Nagy, S. R. Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annu. Rev. Pharmacol. Toxicol.43, 309–334 (2003). CASPubMed Google Scholar
Poland, A., Glover, E. & Kende, A. S. Stereospecific, high affinity binding of 2,3,7,8-tetrachlorodibenzo-_p_-dioxin by hepatic cytosol. Evidence that the binding species is receptor for induction of aryl hydrocarbon hydroxylase. J. Biol. Chem.251, 4936–4946 (1976). CASPubMed Google Scholar
Farrell, K., Safe, L. & Safe, S. Synthesis and aryl hydrocarbon receptor binding properties of radiolabeled polychlorinated dibenzofuran congeners. Arch. Biochem. Biophys.259, 185–195 (1987). CASPubMed Google Scholar
Jensen, B. A., Reddy, C. M., Nelson, R. K. & Hahn, M. E. Developing tools for risk assessment in protected species: relative potencies inferred from competitive binding of halogenated aromatic hydrocarbons to aryl hydrocarbon receptors from beluga (Delphinapterus leucas) and mouse. Aquat. Toxicol.100, 238–245 (2010). CASPubMedPubMed Central Google Scholar
Kolasa, E., Houlbert, N., Balaguer, P. & Fardel, O. AhR- and NF-κB-dependent induction of interleukin-6 by co-exposure to the environmental contaminant benzanthracene and the cytokine tumor necrosis factor-α in human mammary MCF-7 cells. Chem. Biol. Interact.203, 391–400 (2013). CASPubMed Google Scholar
Gillner, M., Bergman, J., Cambillau, C., Fernstrom, B. & Gustafsson, J. A. Interactions of indoles with specific binding sites for 2,3,7,8-tetrachlorodibenzo-_p_-dioxin in rat liver. Mol. Pharmacol.28, 357–363 (1985). CASPubMed Google Scholar
Jin, U. H., Lee, S. O. & Safe, S. Aryl hydrocarbon receptor (AHR)-active pharmaceuticals are selective AHR modulators in MDA-MB-468 and BT474 breast cancer cells. J. Pharmacol. Exp. Ther.343, 333–341 (2012). CASPubMedPubMed Central Google Scholar
O'Donnell, E. F. et al. The anti-inflammatory drug leflunomide is an agonist of the aryl hydrocarbon receptor. PLoS ONE5, e13128 (2010). PubMedPubMed Central Google Scholar
Quattrochi, L. C. & Tukey, R. H. Nuclear uptake of the Ah (dioxin) receptor in response to omeprazole: transcriptional activation of the human CYP1A1 gene. Mol. Pharmacol.43, 504–508 (1993). CASPubMed Google Scholar
Ciolino, H. P., Daschner, P. J. & Yeh, G. C. Dietary flavonols quercetin and kaempferol are ligands of the aryl hydrocarbon receptor that affect CYP1A1 transcription differentially. Biochem. J.340, 715–722 (1999). CASPubMedPubMed Central Google Scholar
Oberg, M., Bergander, L., Hakansson, H., Rannug, U. & Rannug, A. Identification of the tryptophan photoproduct 6-formylindolo[3,2-_b_]carbazole, in cell culture medium, as a factor that controls the background aryl hydrocarbon receptor activity. Toxicol. Sci.85, 935–943 (2005). PubMed Google Scholar
Savouret, J. F. et al. 7-ketocholesterol is an endogenous modulator for the arylhydrocarbon receptor. J. Biol. Chem.276, 3054–3059 (2001). CASPubMed Google Scholar